Neuroblastoma is a cancer of specialized nerve cells that are involved in the development of the nervous system and other tissues. It is the most common extra-cranial solid tumor of childhood and one of the deadliest neoplasms in childhood, accounting for 15% of childhood deaths. Approximately 96% of the cases occur before the age of 10 years.
The disease commonly originates in the adrenal medulla and others sites of sympathetic nervous tissue. The most common occurrence of neuroblastoma is in the abdomen (near the adrenal gland) but it can also be found in the chest, neck, pelvis, or other sites. By the time it is diagnosed, the cancer has usually metastasized to the lymph nodes, liver, lungs, bone and bone marrow. Most neuroblastoma patients have widespread occurrence at diagnosis. Neuroblastomas may compress the spinal cord, causing paralysis.
Neuroblastoma tumors grow aggressively, metastasize, induce angiogenesis and remain resistant to multimodal therapy, demonstrating the need for novel therapeutic strategies that address efficient inhibition of cancer cells and eradication of any remaining refractory microscopic disease. Although high risk patients receive an aggressive regimen of combination chemotherapy, the cancer frequently recurs and up to 80% of patients die of disseminated disease. New and effective cancer treatments are constantly being sought. There is also an urgent need to improve the outcome for patients with the disease, with an increased emphasis for development of new drugs that are highly effective in eliminating aggressive cancer cells while also having insignificant toxicity towards normal cells.
Typical therapies include radiation and drug treatments; unfortunately many are toxic and harmful to normal cells. Although state of the art chemotherapy regimens have been established, the survival benefits still remain negligible (Saijo et al., 2003, Cancer Chemother Pharmacol., 52 Suppl 1:S97-101). For neuroblastoma in particular, there are a number of ongoing Phase III and Phase IV trials for new strategies to treat the disease, yet a safe and effective drug that avoids adverse effects has not yet been found. The cost of the cure can be quite high as the surviving children are exposed to additional health problems because of the long term toxicities of the treatment (Wagner and Danks, 2009, J Cell Biochem, 107:46-53). Certain steroids, in particular progesterone, have been proposed as useful in treatment of certain cancers. For example, progesterone has been proposed as having apoptotic effects against certain hormonally regulated cancer cells, such as from breast, endometrial and ovarian tumors. Natural progesterone has been shown to inhibit the proliferation of breast epithelial cells (Foidart et al., 1998, Fertility and Sterility, 69:963-969) and high natural progesterone levels similar to those seen during the third trimester of pregnancy exhibited a strong anti-proliferative effect on at least two breast cancer cells lines (Formby and Wiley, 1999, Mol Cell Biochem, 202: 53-61; WO99/59595).
It has also been proposed that progesterone deficiency is linked with the occurrence of breast cell carcinoma, for example in women with endogenous progesterone deficiency who have a heightened risk of premenopausal breast cancer occurrence and death (Cowan et al., 1981, Am J Epidemiol, 114:209-217). Boman et al. found that endogenous progesterone plays a role in the control of the breast tumor's proliferation activity (Boman et al., 1993, Cancer, 71:3564-9), and it was also recently shown that a single injection of depot progesterone prior to breast cancer therapy reduced mortality by more than 35% in over 1000 women 65 months after diagnosis and treatment (Badwe et al., 2009, 32nd San Antonio breast Cancer Symposium, December 9-13, TX USA).
In addition to breast cancer, endometrial and ovarian cancer have been linked to progesterone therapy. For example, PCT Publication WO 95/07699 asserts that relatively low levels of serum progesterone, 1 to 6 ng/ml, may be used to prevent endometrial cancer. It has also been shown that progesterone replacement therapy reduces the risk of developing ovarian carcinoma in post menopausal women and is also useful for treating some types of ovarian tumors (Bu et al., 1997, Cancer, 79:1944-1950).
Progesterone therapy has also been proposed in the treatment or prevention of ischemic damage in the central nervous system. Beneficial effects of progesterone have been demonstrated in experimental models of traumatic brain injury, and it has been shown to have a very high safety profile and limited side effects in clinical testing as a treatment for brain injury (Wright et al., 2007, Annals of Emergency Medicine, 49:391-402).
In their study of the use of estradiol and progesterone acting for the prevention of neuronal damage induced by ischaemia in the central nervous system, Lorenz et al. found that the combined and single steroid treatment offered no cell protection to neuroblastoma cells (Lorenz et al., 2009, J Neuroendodrinol, 21:841-9). Indeed, Maggi et al. showed a significant decrease in cell viability of neuroblastoma cells at 10 μM of progesterone (Maggi et al., 1998, Steroids, 63:257-262). Progesterone administration has been shown to suppress cell proliferation and induce apoptosis in malignant mesothelioma cells (Horita et al., 2001, Anticancer Res., 21:3871-3874). Progesterone has been proposed as potentially acting through progesterone receptor A (Inoue et al., 2002, J Clin Endocrinol Metab., 87:5325-5331), although this was not demonstrated.
There remains a need for improved therapy of nervous system tumors such as neuroblastoma that has reduced toxicity over existing treatments. The object of this disclosure is to provide compounds, methods and compositions for treatment or prophylaxis of central nervous system tumors, particularly neuroblastoma and glioblastoma.